Medicament container and method of manufacture thereof

ABSTRACT

A medicament container and a method of manufacturing the container housing at least one individual dose of medicament using a carrier having first and second opposing faces and through walls defining a through hole extending between the first and second opposing faces, the method including inserting the carrier into a mould having an element for protrusion into the through hole from the first face so as to define with the through walls a generally cup-shaped space, filling the generally cup-shaped space with a mould material so as to form a generally cup-shaped insert in the through hole, removing the carrier and insert from the mould, depositing an individual dose of medicament in the generally cup-shaped insert, and sealing the medicament and insert in the through hole by sealing first and second sheets respectively with the first and second faces.

The present invention relates to a medicament container and method ofmanufacture thereof, in particular to containers housing or for housingat least one individual dose of medicament and methods of manufacturethereof.

In the field of dry powder drug delivery, it is known to pre-meterindividual unit doses of medicament into respective compartments of apack, such that individual compartments may be opened and individualunit doses of medicament may be dispensed.

The compartments may be formed as so called blister packs in whichpreformed pockets or blisters are sealed with a lidding foil.

In order to open the compartments, the lidding foil may be pierced usinga sharp edge to puncture the foil, so as to allow air to flow into andout of the compartments. In doing so, the foil is pressed into thecompartment, thereby preventing the compartment from being fully opened,such that it is not fully or repeatably emptied of the powder.

It is also possible to peel the foil away from the base so as to openthe compartments. However, the dispensing devices used to do this aremore complex, since it is necessary to control the tension of thelidding foil and to control accurately the amount of unpeel such thatonly one compartment is opened at a time. Additionally, the compartmentsmust be spaced out so as to simplify the positional control. Thisincreases the size of the blister pack and the dispensing device.

The present invention contemplates the use of generally cup-shapedinserts within respective pockets of the blister pack. Each cup-shapedinsert contains a unit dose of medicament and may be pushed from theunderside of the blister pack so as to burst the lidding sheet outwardlyof the blister pack and expose the medicament for dispensing.

Thus, a member, separate from the base and the lidding sheet, isprovided to rupture the lidding sheet outwardly. In this way, it is notnecessary to provide a complex unpeeling mechanism and the compartmentsof the pack may be spaced closely with respect to one another.Furthermore, the lidding sheet may be opened outwardly of the recessessuch that the recesses become fully opened to air flow and allowcomplete removal of powder from the compartments. By providing theinsert as a rigid member within the compartment to rupture the liddingsheet, pressure from the underside to cause rupturing of the liddingsheet does not compress or agglomerate the medicament within the pack.This is clearly of significant advantage when the medicament is a drypowder form, for instance for inhalation into the lungs or the nasalcavities.

Unfortunately, providing the inserts in the individual pockets of theblister pack increases the complexity and cost of manufacture.Furthermore, there are inherent design restrictions with use of aconventional blister pack where the pockets are formed by deep drawing afilm or sheet.

It is an object of the present invention to provide a medicamentcontainer and a method of manufacture thereof which makes use of theadvantages discussed above whilst reducing the complexity and cost ofmanufacture.

According to the present invention, there is provided a method ofmanufacturing a container for housing at least one individual dose ofmedicament using a carrier having first and second opposing faces andthrough walls defining a through hole extending between the first andsecond opposing faces, the method including:

-   -   inserting the carrier into a mould having an element for        protrusion into the through hole from the first face so as to        define with the through walls a generally cup-shaped space;    -   filling the generally cup-shaped space with a moulding material        so as to form a generally cup-shaped insert in the through hole;        and    -   removing the carrier and insert from the mould whereby an        individual dose of medicament may be deposited in the generally        cup-shaped insert and the medicament and insert sealed in the        through hole by means of first and second sheets sealed        respectively with the first and second faces.

According to the present invention, there is also provided a containerfor housing at least one individual dose of medicament, the containerincluding:

-   -   a carrier having first and second opposing faces and through        walls defining a through hole extending between the first and        second opposing faces; and    -   a generally cup-shaped insert formed in the through hole by        inserting the carrier into a mould having an element for        protrusion into the through hole from the first face so as to        define with the through walls a generally cup-shaped space and        filling the generally cup-shaped space with a moulding material        so as to form the generally cup-shaped insert in the through        hole whereby an individual dose may be deposited in the        generally cup-shaped insert and the medicament and insert sealed        in the through hole by means of first and second sheets sealed        respectively with the first and second faces.

This provides a container which may be filled with medicament accordingto the needs of medicament supplier.

In this respect, according to the present invention, there is alsoprovided a method of providing at least one individual dose ofmedicament in a container using a carrier having first and secondopposing faces and through walls defining a through hole extendingbetween the first and second opposing faces and a generally cup-shapedinsert formed in the through hole by inserting the carrier into a mouldhaving an element for protrusion into the through hole from the firstface so as to define with the through walls a generally cup-shaped spaceand filling the generally cup-shaped space with a moulding material soas to form the generally cup-shaped insert in the through hole, themethod including:

-   -   depositing an individual dose of medicament in the generally        cup-shaped insert; and    -   sealing the medicament and insert in the through hole by sealing        a first sheet with the first face, a second sheet being sealed        with the second face.

The second sheet can be sealed to the second face as part of the methodor the container can be provided with the second sheet already sealed tothe second face such that it is only necessary to perform the steps ofdepositing the individual dose and sealing the first sheet.

According to the present invention there is also provided a method ofmanufacturing a container housing at least one individual dose ofmedicament using a carrier having first and second opposing faces andthrough walls defining a through hole extending between the first andsecond opposing faces, the method including:

-   -   inserting the carrier into a mould having an element for        protrusion into the through hole from the first face so as to        define with the through walls a generally cup-shaped space;    -   filling the generally cup-shaped space with a moulding material        so as to form a generally cup-shaped insert in the through hole;    -   removing the carrier and insert from the mould;    -   depositing an individual dose of medicament in the generally        cup-shaped insert; and    -   sealing the medicament and insert in the through hole by sealing        first and second sheets respectively with the first and second        faces.

According to the present invention there is also provided a containerhousing at least one individual dose of medicament, the containerincluding:

-   -   a carrier having first and second opposing faces and through        walls defining a through hole extending between the first and        second opposing faces;    -   a generally cup-shaped insert formed in the through hole by        inserting the carrier into a mould having an element for        protrusion into the through hole from the first face so as to        define with the through hole a generally cup-shaped space and        filling the generally cup-shaped space with a moulding material        so as to form the generally cup-shaped insert in the through        hole;    -   an individual dose of medicament in the generally cup-shaped        insert; and    -   first and second sheets sealed respectively with the first and        second faces.

It will be appreciated that containers including a plurality of throughholes and inserts may be manufactured in exactly the same way so as toprovide a plurality of individual doses of medicament.

In this way, the insert(s) may be formed and positioned in the containerin the same manufacturing step. A medicament container is providedhaving the advantages discussed above for packs having outwardlybursting inserts and combining this with not only reduced cost andcomplexity but also improved tolerances and reliability. In particular,the tolerance of the volume of the cup-shaped space may be more precisethan previous medicament holding space volumes.

It is also possible to provide pockets with depth to width ratios muchhigher than the conventional maximum for deep drawn blister packaging ofapproximately 2:5. This allows much larger numbers of doses to becontained for a given surface area.

Furthermore, it is possible to produce an insert in each through holehaving a required shape and size such that the insert is a close enoughfit to the through walls to prevent medicament passing therebetween andyet not so tight as to prevent movement of the insert when pushed. Theprotruding element allows the size and shape of the insert cavity to beeasily chosen and changed.

The method may further include the step of forming the carrier with thethrough hole. The carrier may be formed by one of injection moulding,die casting, pressing, extrusion, casting, sintering, stamping, punchingand coining and may be formed from one of polymers, metals, ceramics andcomposites.

The carrier should form a barrier to moisture and, hence, be completelyimpermeable. This may be achieved by forming the carrier from ametalised plastics material or aluminium.

Aluminium is a relatively cheap light material which may be formedeasily into any appropriate shape with the required through holes.

The insert may be formed from a thermoplastic or thermosetting polymer,resin or any other material that can be injected as a fluid and thenconverted to a solid when in situ. For instance, the insert may beformed from one of a polymer, elastomer and monomer.

This allows the insert to be moulded easily within the through hole ofthe carrier.

Preferably, the first and second sheets are formed from aluminium. Theymay be aluminium composites or laminates and provide good moistureresistance and may easily be hermetically sealed to the carrier,particularly when this is also aluminium.

Preferably, the shape and size of the element is chosen to define thevolume and shape of the space defined within the insert.

In this way, the form of the mould is able to define features of theinternal surface of the insert, including volume, shape, etc. Thisallows the insert cavity to be moulded with a precise volume, thusenabling the cavity volume to be used for the metering of powder orfluid which is to be contained. Furthermore, the volume of the insertcavity can easily be changed by changing a single tooling component,i.e. the element, of the mould. The cup-shaped insert, by surroundingthe housed medicament, also provides thermal insulation to themedicament during heat sealing of a first sheet to the first face.

Preferably, the fit of the insert in the through hole is controlled bycontrolling at least one of the injection pressure, the injectiontemperature, the surface finish of the through walls and a draught angleof the through walls.

This allows the insert to be fitted in the through hole such thatmedicament cannot pass between the insert and the through walls butallowing the insert to be pushed along its axis out of the through hole.Furthermore, the insert may be held in place in the through hole by itscontact with the through walls without preventing the insert from beingpushed out of the through hole.

Preferably, the adhesion of the insert in the through hole is controlledby controlling at least one of the preheat temperature of the carrier,the material of the insert and the fit of the insert, for instance asdescribed above. The surface finish of the through walls will affect theinsert's resistance to movement. Indeed, the through walls may be formedwith specific features, such as protrusions or indents, around which theinsert must deflect when being pushed axially out of the through hole.

Preferably, the generally cup-shaped space is filled with the mouldingmaterial from the second face.

Alternatively, the cup-shaped space can be filled with moulding materialfrom the first face, for instance through a filling passage in theprotruding element. In this way, the second sheet can already be sealedto the second face before moulding of the insert. Alternatively, thesecond sheet could be placed in the mould with the carrier and sealed tothe carrier during the step of moulding the insert.

Thus, the insert may be filled in situ in the carrier.

Preferably, the mould at the second face is generally flush andco-planar with the second face. Thus, the closed end of the cup-shapedinsert is generally flush and co-planar with the second face.

Although it is preferred that the wall of the insert ends in closeproximity to the top edge of the through-hole, the mould could extend upinto the through hole from the second face so that the insert isrecessed behind the second face. However, construction of the mould andthe processing is made more straightforward when the mould is co-planarwith the second face. Furthermore, this results in the closed end of theinsert being immediately accessible for pushing the insert out throughthe first face. In this respect, the mould could alternatively be formedsuch that the closed end of the insert protrudes beyond the second face.

Preferably, the insert fills the space of the through hole. This is aresult of the process of moulding the insert in situ and ensures thatthe insert fits well in the through hole, is guided properly when movedto burst the first sheet and wastes no space. In particular, the insertfills completely a space between the through walls so as effectively, asfar as particles of medicament are concerned, to seal the through hole.In other words, the periphery of the insert fits with the through wallsto prevent particles, typically for example drug particles of the orderof one micron for use in a dry powder inhaler, passing therebetween.

Preferably, the medicament is in dry powder form, suitable forinhalation to the nasal cavities or lungs.

Containers of the present invention are particularly suitable for suchuse.

According to the present invention, there is also provided a method ofmanufacturing a carrier including punching out the through holes.Preferred techniques for this are described below.

The invention will be more clearly understood from the followingdescription, given by way of example only, with reference to theaccompanying drawings, in which:

FIGS. 1( a) to (e) illustrate containers constructed according to thepresent invention;

FIG. 2 illustrates a cross section of a pocket constructed according tothe present invention;

FIG. 3 illustrates the pocket of FIG. 2 with the insert pressed througha face;

FIG. 4 illustrates a carrier with a protruding insert constructedaccording to the present invention;

FIG. 5 illustrates a carrier for use with the present invention;

FIG. 6 illustrates the process of moulding an insert with a carrieraccording to the present invention;

FIGS. 7( a) and (b) illustrate carriers with shaped through wails.

FIG. 8 illustrates in greater detail various tolerance features of apocket similar to that of FIG. 2;

FIG. 9 illustrates the insert of FIG. 8 being pushed out of its throughhole into a supporting anvil plate; and

FIGS. 10( a) to (c) illustrate flashing produced during moulding.

Containers constructed according to the present invention may take anumber of different forms. In particular, they may include one or aplurality of pockets for respective doses of medicament. These pocketsmay be arranged in arrays of any desired pattern and may be formed incarriers of any desired shape.

FIGS. 1( a) to (e) illustrate various examples.

In all cases, a carrier 10 is provided with a lidding sheet 12 on afirst face and a lidding sheet 14 on a second face. The sheets 12 and 14seal one or more through holes in the carrier 10. Once sealed with thesheets 12 and 14, the through holes will not be visible. However, to aidin an understanding of the construction, the through holes are signifiedin the figures by dashed lines. Thus, it will be seen that the containerof FIG. 1( a) includes a single pocket, the container of FIG. 1( b) hasa strip-like or tape-like form with an elongate array of pockets, thecontainer of FIG. 1( c) is planar with a two-dimensional array ofpockets, the container of FIG. 1( d) is disk-shaped with acircumferential array of pockets and the container of FIG. 1( e) is drumshaped with a peripheral array of pockets.

FIG. 2 illustrates a cross section through a carrier showing one pocket.Through-walls 16 in the carrier 10 define a through hole 18. Formedwithin the through hole 18 is a generally cup-shaped insert 20. Asillustrated, the outer volume of the cup-shaped insert 20 generallyfills the through hole 18. Indeed, the closed end 22 of the insert 20 isgenerally co-planar and flush with the second face of the carrier 10.

As illustrated, the generally cup-shaped insert 20 has a recessed innervolume 24 forming a space in which to house a medicament, such as apowder 26. The open end 28 of the insert 20 forms a generally peripheralwall adjacent the lidding sheet 12.

As illustrated in FIG. 3, in use, pressure is applied to the closed end22 of the insert 20 from the second face of the carrier 10 through thesheet 14. In this way, the insert 20 is moved upwardly out of thethrough hole 18 such that the walls of the open end 28 rupture the sheet12. In this way, access is given to the medicament within the space 24of the insert 20 such that it may be dispensed as required.

FIG. 4 illustrates an insert 20 protruding from the first face of acarrier 10. For simplicity, this is illustrated without the sheets 12and 14.

As will be appreciated from the following description, the constructionof the insert 20 in the through hole 18 is particularly advantageouswith regard to its method of manufacture. In particular, the insert 20is moulded in situ in the carrier 10.

First, a carrier 10 is provided having one or more through holes 18.FIG. 5 illustrates for simplicity a carrier 10 having only one throughhole. However, it will be appreciated that other carriers, for instancethose illustrated in FIGS. 1( a) to (e) can also be provided. Thecarrier 10 may be manufactured from any suitable material, such aspolymers, metals, ceramics, composites, etc. The choice of material willdepend on the required moisture resistance properties, flexibility,weight, cost, etc. Since, as will be described below, the carrier 10 isalso to be provided within a mould such that the insert 20 is moulded insitu, it is also important that the material of the carrier 10 be chosento allow this process to be conducted.

In a preferred embodiment, the carrier 10 is constructed from a lowwater permeability plastic or composite plastic or aluminium.

The carrier 10 may be manufactured by any appropriate process, such asinjection moulding, die casting, pressing, extrusion, casting,sintering, stamping, punching or coining. In particular, depending onthe material chosen for the carrier 10, a process may be chosen which iscapable of forming through holes 18 suitable for accepting the inserts20.

The carrier 10 may be formed with through holes of any desired shape andnot necessarily circular as illustrated in the figures. Indeed, for theembodiment of FIG. 1( d), it is preferred that the holes are elongate ina radial direction. For moisture resistance, there will be a minimumspacing between adjacent holes, but more efficient packing is obtainedif the circumferential extent of the holes is reduced and the radialextent increased.

It is required that the insert 20 be able to slide along its axis withinthe through hole 16 and out of the first face. However, otherwise, theshape of the through hole 16 may be designed freely and the process formanufacturing the carrier 10 chosen accordingly.

The insert 20 is formed from a moulding process, preferably an injectionmoulding process.

The carrier 10 is inserted into a mould for forming the insert 20. Asillustrated in FIG. 6, the carrier 10 is located between a first mouldtool 40 and a second mould tool 42. The first mould tool 40 generallyseals with the first face of the carrier 10 and the second mould tool 42generally seals with the second face of the carrier 10. In this way, amoulding cavity is formed within the through hole 18.

A feed channel 44 is formed in the second mould tool 42. This allowsmoulding material to be injected into the cavity formed by the throughhole 18.

As illustrated, the first mould tool 40 is formed with a protrudingelement 46 which extends from the first face of the carrier 10 into thethrough hole 18. An outer surface 48 of the protruding element 46defines the inner surface of the insert 20 to be formed by the mould. Onthe other hand, the through walls 16 define the outer peripheral wallsof the insert 20 and the face of the mould tool 42 defines the closedend of the insert 20. As illustrated, the resulting insert is formedwith the cup-shaped space 24 for housing medicament and outer peripheralwalls 28 for rupturing the first sheet.

It should be appreciated that, by this method, the fit of the insert 20in the carrier 10 is independent of the shape and size of the insertcavity 24 formed by the protruding element 46. Similarly, the insertcavity 24 may be designed freely and is independent of the fit of theinsert 20 in the carrier 10.

The carrier is placed into the tooling of an injection mould such thatthe carrier itself forms part of the mould cavity. The form of the mouldtool, in particular the protruding element 46 is able to define featuresof the internal surface of the insert 20 including volume, shape, etc.This allows the insert cavity 24 to be created with a precise volume.This is particularly advantageous when the cavity volume is used tometer the required amount of medicament, for instance powder or fluid,which is to be contained. In particular, the insert cavity 24 may becompletely filled with medicament, such that the volume of the insertcavity 24 is chosen to be the volume required for a single dose ofmedicament.

It will also be appreciated that, using this method of manufacture, thevolume of the insert cavity 24 may be easily changed by changing a smallpart of the moulding tool, i.e. the protruding element 46. Indeed, itbecomes easy to provide a variety of different insert cavity volumes,even within the same container.

As will be discussed in further detail below, the fit of the insert 20in the carrier 10 is controlled by altering a number of parametersincluding the injection pressure and temperature, the surface finish ofthe internal surface, i.e. the through walls 16, of the through hole 18or the draught angle on the through hole 18. Furthermore, the throughwalls can be formed with specific features, such as recesses 50 orprotrusions 52, as illustrated in FIGS. 7( a) and (b), to resistmovement of the insert.

In order to achieve good performance for specific embodiments of theconcept, it is thus desirable to consider the requirements for the formof the holes in the carrier plate.

For the embodiment illustrated in FIGS. 2 and 3 where the insert 20 isto be pushed through the foil 12 on the first face such that it rupturesthe foil cleanly, the requirements for the hole in the carrier platewill be described with respect to FIG. 8 and FIG. 9 where FIG. 8 showsthe special requirements of the holes and FIG. 9 shows the insert beingpushed up into an anvil plate 62 which controls the breaking of thefoil. The anvil plate 62 supports and holds the foil on the top surfaceso as to provide a controlled rupturing of the foil.

The peripheral radius 57 of the through hole of the carrier plate 56 atthe top surface, through which the insert 55 is to be pushed, may havean effect on the ultimate performance and usability of the container. Ifthe radius is too small and the corner too sharp, it could tear the foil59 when it is pressed down to seal it to the carrier 56. However, if theradius is too large and the corner too round, the top of the insert 63will be formed into a peripheral lip which will catch on the corner 64of the anvil plate 62 preventing the insert from moving up.

Preferably the radius 57 should be more than 0.025 mm and less than 0.10mm for an insert wall thickness of 0.3 mm (not exceeding 30% of the wallthickness).

The peripheral radius 58 of the through hole at the bottom surface fromwhich the insert is to be pushed may also have an effect on theperformance and usability of the container. If the radius is too smalland the corner too sharp, then it may damage the foil 60 on sealing.However, if the radius is too large and the corner too round, the baseof the insert wall will form a peripheral lip extending wider than thewidth of the hole and the force needed to push the insert up becomes toolarge.

Preferably, the radius 58 falls within the same range as that describedabove for radius 57. Indeed, the radius 58 may be substantially the sameas that for radius 57.

Typically, manufacturing methods for the holes in the carrier plate 56can leave burrs, i.e. sharp bits of material, on the corners 57 and 58.In particular, where the holes are machined, top and bottom corners 57,58 can have burrs and, where the holes are pierced, punched, broached orpressed, then there will be a rounding of the entry and burrs on theexit side.

Burrs that extend beyond the top or bottom surfaces are disadvantageous,since they can puncture the foil 59 or 60.

Burrs that extend into the hole can become trapped in the insert 55during the moulding process and prevent the insert moving when it ispushed. Thus, preferably the overall manufacturing process includes theremoval or reduction of any burrs caused in the manufacture of thethrough holes. In particular, any burrs extending beyond the top andbottom surfaces should be reduced to less than 25 microns (preferablyless than 5 microns) and any burrs extending into the through holesshould be reduced to less than 100 microns (preferably less than 50microns).

The roughness of the inner wall 65 of the through hole also has aneffect on the fit of the insert 55 in the carrier 56. If the wall 55 istoo rough, then the frictional resistance to movement of the insert wallwill be too high. On the other hand, if the wall 65 is too smooth, theinserts may fall out.

The method of manufacture of the hole will influence the form of theroughness on the pocket walls. Machining will produce grooves in theplane of the corner and punching/blanking will produce groovesorthogonal to the carrier plane.

Punched holes are preferred since they can provide the best finish. Thegrooves across the plate provide some friction but allow smooth movementto push out the insert.

Roughness in the range of 0.03 to 0.3 of the wall thickness of theinsert is preferred.

Care may be required when punching holes to avoid the material tearingtowards the exit face. This can produce a ridge around the hole that canproduce excessive resistance to the insert motion.

The following description relates to the preferred manufacturing processof punching an aluminium sheet. For example, a carrier of the form shownin FIG. 1( d) may be provided as a disc with a circular array of holeswith substantially parallel sides right though the disc.

This form of carrier could be made by machining the holes with drillingor milling operations. Conventional milling using an automated millingsystem (CNC) is possible but can be relatively expensive. Drilling couldbe used relatively cost effectively for circular holes, but not forother shapes. A custom machining tool using multiple milling heads couldbe cost effective for some hole shapes.

The present application recognises that, where the material andthickness of the plate allow, holes could be punched through thematerial. Aluminium is a material in which holes may be punched forthicknesses up to 5 mm. This approach allows the punching of any numberof holes simultaneously with the appropriate tool design. This istherefore a highly advantageous and cost effective method of range 1 secto 10 sec.

Punching a hole in a thick plate can produce a hole where the materialsurrounding the hole is deformed. In particular, there may be roundingof the entry edges, tearing of the material along the walls of the hole,burrs on the exit edge and/or depressions in the surfaces surroundingthe hole.

The present application proposes a refinement to the punching process toachieve high quality for hole required to accommodate the inserts.Several approaches may be used, the choice depending specifically on thematerials and dimensions required.

One approach is to use what might be termed fine blanking and to providethe material to be punched with close toleranced clamping all around thehole and to use a press and tooling that ensures precise control of thegaps between the punch tool and the surrounding clamps. With this levelof accuracy, it is possible to reduce the rounding and tearing whenusing aluminium sheet material up to 3 mm thick.

Where deeper holes are required, then broaching may be necessary toachieve the required tolerance control. An initial hole is punched andthen this is progressively widened by a series of cutters each just alittle larger than the previous one.

Whatever punching approach is used, it is preferred to ensure that nosharp burrs remain at the exit corners. A finishing process is thereforepreferred to ensure no burrs remain.

This may use: tumbling with grit, stones or balls; sand or gritblasting; electro etching/de-burring; and/or chemical de-burring. Thetechnique selected will depend upon the requirement for the surfacefinish on the walls and surfaces for the carrier plate. For example,tumbling with grit may roughen all surfaces or produce random scratcheson the surfaces. Where foil is to be sealing to the surface to provide abarrier, then any scratches deeper than the bonding later between thefoil and surface would degrade the integrity of the seal. Alternatively,a finishing process that gives a very smooth surface might not providesufficient friction for good adhesion of foil or to retain the insertsin place before foiling.

It is also possible to punch a sheet of plastics material. Themanufacturing process required for punching plastics material to therequired tolerance is different to that required for a metal. Taking forexample 3 mm HDPE material to be punched for the carrier described inFIG. 1( d), punching can leave strings of material around the exit hole.This is because HDPE is a much softer material than aluminium and thepressure wave that is produced ahead of the cutting tool can causematerial to extrude through the gaps between the press tool and thesupport plate.

Thus, to use punching with a plastics material, different tools andconditions will be required for each material and hole size.

The present application considers the following approaches: cooling theplastic to increase its stiffness sufficiently to enable simple punchingwork; broaching coring; punching of a core followed by a finishingoperation using a shaped knife blade to shave a thin layer off thewalls; and/or a heated knife blade to locally melt the plastic at thecutting edge.

For the case of producing round ended elongated holes of 2.5 mm widthand 8.0 mm length in 3 mm thick HDPE, a two stage process is preferred.Initially, a rounded ended hole 1.9 mm wide 7.4 mm long is punched. Thisis followed by removing the remaining 0.3 mm of wall using a bladeformed in the desired hole shape. To prevent stringing at the exit hole,the 3 mm HDPE sheet is clamped between rigid plates with an additionalsheet of plastic material on the exit face. The blade is driven throughthe HDPE sheet to penetrate into the plastic sheet underneath.

Typically, the sheet thickness is between 0.25 mm and 1.0 mm and theblade penetrates a minimum of 0.2 mm into it.

The cutting edge of the blade is preferably angled on the hole side andplane on the outside. The centre of the cutting blade is preferablyhollow to allow space for the cut material to occupy during the cuttingprocess without it generating a lateral force on the blade. This swarfcan be ejected after the cut.

Apart from punching, it is also possible to mould a plastics materialcarrier.

Taking the example of FIG. 1( d), it is possible to injection mould thecarrier plate as an alternative to punching it as described above. Thereare advantages in simplifying the foil sealing process if the surfacesto which the foil will be sealed are flat. It is therefore desired that,for the moulding of such plates, the moulding process minimises anyejector pin marks, sink marks or gate flashing that prevent thesesurfaces being flat. For the example described, it is preferred to havea flatness of 50 microns or less, with 10 microns further preferred.

To achieve this, the moulding conditions should be optimised for theparticular tool being used and large area ejector surfaces anddistributed gating should be used to minimise the flow distances.

The angle of the inner wall 65 can also be considered.

Holes can be fabricated with the angle of the walls 65 of the hole atany required value. Punching produces walls which are nominallyorthogonal to the faces of the carrier 56 and this is preferred in mostcases.

However, holes which are slightly larger at the face out of which theinsert will be pushed provide less resistance whilst retaining theability to guide the motion of the insert.

This may be required for some embodiments.

Where required, such holes can be machined or, with the appropriateconditions and materials, a sufficient angle may be achievable even witha punching manufacturing method.

The preferred wall angle for the current embodiment is between straight(90 degrees to the face) and 3 degrees from straight, more preferably 1degree.

The insert moulding process requires the carrier plate to be placedinside a mould tool designed to restrict the plastic to the requiredinsert form.

Where the carrier plate is made from an incompressible material and themould tool closes on itself then, if the thickness of the carrier plateis less than the space allowed for it, there will be a gap into whichthe plastic may flow causing flashing.

Where the container is used for an inhalable material, any flashingcould break free during use and be inhaled. This would not beacceptable.

To prevent this, the tolerance on the thickness of the carrier platemust be tight enough never to allow a gap into which plastic would flowduring the moulding.

Preferably, this is less than 0.1 mm, more preferably 0.05 mm or less,where such tolerance control is not achievable, the mould tool could bedesigned to form a seal against the carrier plate surface rather thanagainst another part of the mould tool.

Whilst the method of manufacture as described above could be applied toholes of any shape, there are effects of the shape that can beconsidered in the overall design.

The insert moulding material fully fills the allowed volume duringinjection of the plastic material. However, as the material cools andsolidifies, it may expand or contract. The amount of this change can becontrolled by the material and process conditions.

If there is too much shrinkage, then the inserts may be loose and mayfall out. Also, gaps may be formed between the insert wall and the holewall and the contained material, such as powder, may enter these gaps.

If there is too much expansion, then any straight sided walls will bowinwards, reducing the volume of the pocket. Similarly, the insert maystick in place.

Walls that have a convex shape will be more tolerant of any expansion,because they will not buckle inwards under low levels of compression.This is in contrast to straight or concave walls.

However, for the embodiment shown in FIG. 9, the pocket shape and anvil62 are designed to rupture the foil around three sides causing a flap offoil 61 to pivot upwards on the fourth side. This is achieved byallowing a gap between the anvil edge and the edge of the pocket on thefourth side where the foil will pivot.

This operation, however, is made more reliable if the pivoting side issubstantially straight. Thus, for this embodiment, the material andprocess for forming the pockets is preferably chosen to avoid anysubstantial expansion on cooling.

In the preferred manufacturing process, the carrier plate is placed in amould tool so that part of the mould tool wall is located in the centreof the hole with a gap around it that is filled with plastic to form theinsert. However, if the protrusion is not exactly centred on the holethen one wall will be thicker than its opposing wall. At some point, thethickness of the thin wall will not meet its mechanical strengthrequirements or even may not be sufficiently thick to allow it to fillfully with plastic during the moulding process.

There is therefore a tolerance requirement for the size and position ofthe hole with respect to the protuberance in the mould tool.

It has been recognized that it becomes difficult to mould walls thinnerthan 0.2 mm. Thus for a wall thickness of 0.3 mm the positionaltolerance should be ±0.1 mm.

Specific tolerances for particular embodiments can be determined by theoverall mechanical requirements.

Where single holes are being insert moulded, the tolerance requirementscan easily be achieved. However, where an array of holes on a commoncarrier plate are to be moulded in one shot, the achievement of thattolerance may be more difficult. For example, a square array with a 100mm side length and with square inserts with 0.3 mm walls preferably hasa positioned alignment of ±0.05 mm and an angular alignment of 2arc-minutes (0.03 degrees).

The alignment requirements can be reduced by careful design of thearray. For example, a circular array of 100 mm diameter with insertsthat are longer in the radial direction than in the circumferentialdirection is much less sensitive to angular misalignment than a squarearray. Furthermore, it is mechanically easier to centre mould tools fortwo circular arrays than it is for square ones.

The adhesion of the insert 20 in the through hole 18 will additionallydepend on a number of parameters including the pre heat temperature ofthe carrier 10 and the materials chosen for the insert 20 and carrier 10as well as the parameters affecting the fit described above. The insert20 is preferably made from thermoplastic or thermosetting polymer, resinor any material that can be injected as a fluid and then converted to asolid when in situ, for instance a polymer, elastomer or monomer.

Where the carrier plate is made of a metal it will not be effected bythe insert moulding process.

However carrier plates of plastic may also be used. In this case, it isnecessary to consider the interactions that can occur during the insertmoulding process.

If the melting point of the carrier plate material is much higher thanthe temperature of the insert plastic when it is injected then therewill be little interaction.

However, where the carrier plate melting point is similar or lower thanthat of the insert material, the process must be controlled to minimisemelting of the carrier plate material around the pocket.

When a sealing foil is to be welded to the carrier plate, this requiresmelting of the surface in contact with the foil. There is then arequirement to use a carrier plate material with a lower melting pointthan that of the insert material so as to avoid damaging the insertduring the sealing process.

Counter-intuitively, it has been found possible to successfully mouldpolypropylene inserts into a polyethylene carrier plate even though themelting point of polypropylene is much higher than polyethylene.

This is achieved by optimising the time, pressure and temperature of theprocess for the particular geometry and materials being used. For thematerials referred to above with inserts with walls 0.3 mm thick in a 3mm thick carrier plate, the moulding parameters below were found to bepreferred:

Pressure - 100 bar Temperature - 215 degrees Celsius Time -  2 seconds

However, with these conditions, a small amount of melting of the carrierplate could occur and which could lead to adhesion between the insertsand the carrier plate. It has been found that this bond could be brokenwithout damage to either component but this requires a higher force thanis desirable for routine operation. To overcome this, each insert can bepressed partially out of its hole so as to break the bond. It can thenbe reset to its original location. Subsequently, it can be moved with amuch lower force.

Typically, the force needed to initially release an insert of area 20mm² in a 3 mm thick carrier plate of HDPE is between 50N and 100N.Following the initial bond breaking, the force required can be less than30N.

Careful selection of gating technique will help to avoid gating marks onthe insert 20 as well as separating the moulding sprue from thecomponents.

The plastic flows into the mould during insert moulding through one ormore channels in the walls of the mould tool. When the mould is full,one or more gates close off the plastic in the mould from the stillmolten plastic in the feed channels.

It is difficult to make the surface of the insert smooth at the gatelocation and flashing or pips may occur. In the preferred embodiment,the gate area is on the bottom of the insert over which foil will beapplied to seal the compartment.

Flashing or sharp pips extending beyond the surface may risk puncturingof the foil.

A gating arrangement to prevent this is therefore preferred. An exampleof this is shown in FIG. 10.

FIG. 10( a) shows the flashing that can occur when the gate is locatedat the surface of the component.

FIG. 10( b) shows a variation where the gate is positioned slightlybelow the surface so that a hollow is formed within which the flashingcan be recessed. This may be sufficient. However, there is still achance that some sharp edge will still be above the surface.

FIG. 10( c) shows the situation where the protruding material has beenflattened and deformed into the recess. This may be achieved by heat,ultrasonic or other means of locally melting the plastic and pushing itbelow the surface using a hard flat tool.

In this way it can be ensured that no sharp edges will be above thesurface to damage the foil.

Thus, it is possible to produce an insert 20 in each through hole 18with a required shape such that the insert 20 is a close fit to thewalls 16 of the carrier 10. This prevents the medicament penetratingpast the insert 20, but allows the insert to move freely when pushedfrom below. The technique is generally suitable for the manufacture ofassemblies which contain a multiple of components with sliding orrotating fits which would otherwise have to be individually assembled.It thus represents a saving in materials handling and assembly costs.

When the carrier 10 is removed from the mould 40,42, it contains theinsert 20. In accordance with the parameters discussed above, in thepreferred embodiment, the insert 20 is held resiliently in place withinthe carrier 10. In this way, no additional process steps are required tomaintain the insert 20 in position.

The insert or inserts of the carrier 10 may then be filled withmedicament. The medicament may be provided in any suitable form, forinstance as a tablet, powder or liquid. However, the containerconstructed as described is particularly advantageous for use with drypowder.

The medicament may be dispensed into the insert cavities 24 of theinserts 20 from a device which dispenses doses of a predeterminedquantity. However, as mentioned above, the insert cavity 24 can bechosen with a predetermined volume such that filling the insert cavities24 results in the container housing the required doses of medicament.

The lidding sheets 12 and 14 may then be fixed to the first and secondfaces of the carrier 10 so as to seal the inserts 20 and medicamentwithin the through holes 18. Preferably, the sheets are hermeticallysealed. This is particularly advantageous for dry powders. The liddingsheet may be constructed of aluminium foil, although any other suitablematerial which provides the required barrier properties may be used.

It is also possible for the second sheet to be sealed to the second facebefore the step of filling with medicament.

Furthermore, as an alternative to the method discussed above, thecup-shaped space may be filled with moulding material from the firstface, for instance via a filling channel in the projecting element. Inthis case, it is possible to seal the second sheet to the second facebefore or during the moulding step. If the second sheet is placedbetween the lower mould and the carrier 10, then it is possible to sealit to the carrier at the same time as filling the cup-shaped space withmoulding material, for instance by heating.

1. A method of manufacturing a container for housing at least oneindividual dose of medicament using a carrier having first and secondopposing faces and through walls defining a through hole extendingbetween the first and second opposing faces, the method including:inserting the carrier into a mould having an element for protrusion intothe through hole from the first face so as to define with the throughwalls a generally cup-shaped space; filling the generally cup-shapedspace with a moulding material so as to form a generally cup-shapedinsert in the through hole; and removing the carrier and insert from themould whereby an individual dose of medicament may be deposited in thegenerally cup-shaped insert and the medicament and insert sealed in thethrough hole by means of first and second sheets sealed respectivelywith the first and second faces.
 2. A method of manufacturing acontainer housing at least one individual dose of medicament using acarrier having first and second opposing faces and through wallsdefining a through hole extending between the first and second opposingfaces, the method including: inserting the carrier into a mould havingan element for protrusion into the through hole from the first face soas to define with the through walls a generally cup-shaped space;filling the generally cup-shaped space with a moulding material so as toform a generally cup-shaped insert in the through hole; removing thecarrier and insert from the mould; depositing an individual dose ofmedicament in the generally cup-shaped insert; and sealing themedicament and insert in the through hole by sealing first and secondsheets respectively with the first and second faces.
 3. A methodaccording to claim 1 further including: forming said carrier with saidthrough hole.
 4. A method according to claim 3 further including:forming said carrier by one of injection moulding, die casting,pressing, extrusion, casting, sintering, stamping, punching and coining.5. A method according to claim 3 further including: forming said carrierfrom one of polymers, metals, ceramics and composites.
 6. A methodaccording to claim 3 further including: forming said carrier from amoisture impermeable material such as a low permeability plastic,composite or aluminium.
 7. A method according to claim 1 furtherincluding: forming said insert from one of a polymer, elastomer andmonomer.
 8. A method according to claim 1 further including: formingsaid first and second sheets from aluminium or any low permeabilitysheet material such as Aclar, CTE or Barrex.
 9. A method according toclaim 1 wherein the fit of the insert in the through hole is controlledby controlling at least one of the injection pressure, the injectiontemperature, the surface finish of the through walls and a draught angleof the through walls.
 10. A method according to claim 1 wherein thesealing of the insert in the through hole is controlled by controllingat least one of the preheat temperature of the carrier, the material ofthe insert and the fit of the insert.
 11. A method according to claim 1wherein the mould at the second face is generally flush and co-planarwith the second face.
 12. A method according to claim 2 wherein thegenerally cup-shaped space is filled with the moulding material from thesecond face.
 13. A method according to claim 1 wherein the second sheetis sealed to the second face before or during the step of filling thecup-shaped space with moulding material.
 14. A method of manufacturingaccording to claim 1 further including varying the size of the elementso as to vary the volume of the cup-shaped space between differentcontainers.